Blood cells are derived from hematopoietic stem and progenitor cells in the bone marrow. During the process of differentiation, a pluripotential stem cell gives rise to progenitor and effector cells that have a more limited developmental repertoire, and which may give rise only to cells within a particular lineage. The common myeloid progenitor cell is the precursor of megakaryocytes, erythrocytes, granulocytes, macrophages, dendritic cells, and mast cells. These cells comprise the innate immune system, which is involved in antigen presentation, phagocytosis, and other non-antigen specific responses.
Macrophages are one of the three types of phagocytic cells in the immune system. They are the mature form of monocytes, which circulate in the blood and differentiate continuously into macrophages upon migration into the tissues. Dendritic cells are also phagocytic, and are specialized to take up antigen and display it for recognition by lymphocytes. Mast cells also differentiate in the tissues. They mainly reside near small blood vessels and, when activated, release substances that affect vascular permeability. Although best known for their role in orchestrating allergic responses, they are believed to play a part in protecting mucosal surfaces against pathogens.
There are three types of granulocyte, all of which are relatively short lived and are produced in increased numbers during immune responses, when they leave the blood to migrate to sites of infection or inflammation. Neutrophils, which are the third phagocytic cell of the immune system, are the most numerous and most important cellular component of the innate immune response: hereditary deficiencies in neutrophil function lead to overwhelming bacterial infection, which is fatal if untreated. Eosinophils are thought to be important chiefly in defense against parasitic infections, because their numbers increase during a parasitic infection. The function of basophils is probably similar and complementary to that of eosinophils and mast cells.
Patients suffering from various diseases and therapies may have a deficiency on one or more of these myeloid lineage cells, which deficiency can result in increased susceptibility to bacterial and fungal infections. Leukopenia is usually characterized by a reduced number of blood neutrophils, although a reduced number of lymphocytes, monocytes, eosinophils, or basophils may also contribute to the decreased total cell count. Neutropenia accompanied by monocytopenia and lymphocytopenia is often a more serious disorder than neutropenia alone. Thrombocytopenia can also be a problem for myelosuppressed patients, stemming from failed megakaryocyte production. Severe thrombocytopenia results in a typical pattern of bleeding. Platelet transfusions can be used, but with discretion, because they may lose their effectiveness with repeated use owing to the development of platelet alloantibodies.
For example, patients undergoing hematopoietic cell transplantation (HCT) receive myeloablative doses of chemo-radiation therapy that lead to depletion of hematopoietic stem cells (HSC), progenitor cells and mature cells, thus leading to a phase of treatment related pancytopenia. The reconstitution of a functional immune system after HCT is dependent upon the de novo regeneration of all hematopoietic lineages from HSC and progenitor cells and on the function of mature cells contained in the graft. Infections after HCT typically follow a reproducible time pattern correlating with the kinetics of immune reconstitution, and despite aggressive treatment, the mortality rate of infections in the absence of immune reconstitution can be very high.
Drugs are one of the most common causes of neutropenia. Drug-induced neutropenia has several underlying mechanisms (immune, toxic, idiosyncratic, or hypersensitivity reactions), including severe neutropenia that predictably occurs after large doses of cytoreductive cancer drugs or radiotherapy and from that caused by viral infections. Cytotoxic chemotherapy induces neutropenia because of the high proliferative rate of neutrophil precursors and the rapid turnover of blood neutrophils. Impaired neutrophil production can also occur when leukemia, myeloma, lymphoma, or metastatic solid tumors infiltrate and replace the bone marrow. Tumor-induced myelofibrosis may further extenuate neutropenia. Myelofibrosis can also occur from granulomatous infections, Gaucher's disease, and radiotherapy.
Patients whose neutropenia is secondary to acquired disorders of production arising from cancer or from chemotherapy are more likely to develop serious bacterial or fungal infections because their overall immune system is compromised. The integrity of the skin and mucous membranes, the vascular supply to tissue, and the nutritional status of the patient also influence the risk of infections in acute neutropenia. Patients may also suffer from genetic or primary deficiencies of myeloid cells and are highly susceptible to infection as is seen, for example, in children with chronic granulomatous disease.
The treatment and prevention of infections, particularly in patients suffering or at risk of myeloid cell deficiencies, are of great medical concern. The present invention addresses these issues.